TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis

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BACKGROUND: Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis.

METHODS: We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions.

RESULTS: We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10(-6)). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. CONCLUSIONS: Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.).

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遗传与发育协同创新中心发现导致先天性脊柱侧凸的新机理

2015年1月7日,《新英格兰医学杂志》(The New England Journal of Medicine)以原创性论文(Original Article)的形式,发表了由复旦大学与中国医学科学院北京协和医院共同牵头,联合首都儿科研究所、美国Baylor医学院等多家国内外单位合作完成的研究论文“TBX6基因无效变异联合常见亚效等位基因导致先天性脊柱侧凸(TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis)”。

先天性脊柱侧凸是由于胚胎期脊柱发育异常导致的三维畸形,患者可有腰背痛、丧失劳动力甚至残疾,给社会和家庭造成了严重负担。但该病的病因长期不明。已有研究提示DNA变异在先天性脊柱侧凸发病过程中起重要作用,但未发现主要致病基因。

该研究采用“比较基因组杂交芯片”技术,首次解析了先天性脊柱侧凸患者的全基因组拷贝数变异,发现高达7.5%的散发先天性脊柱侧凸患者在基因组16p11.2区域内有大片段DNA的缺失,进一步的基因测序分析将缺失区域内的TBX6基因确认为致病基因。在机制探寻中,该研究发现TBX6 基因的缺失、无义、移码等不同形式的罕见变异本身还不足以导致先天性脊柱侧凸,通常需要联合一个常见的TBX6亚效等位基因来共同致病。这些发现不仅提示了TBX6是迄今最重要的先天性脊柱侧凸致病基因,而且揭示了TBX6基因致病的复合遗传机理,为先天性脊柱侧凸早期诊断及遗传咨询提供了理论依据。这一研究突破了疾病的遗传学研究中占主导地位的“常见变异致常见疾病”的理论框架,揭示了常见变异与罕见变异共同作用导致疾病发生的新机理。

复旦大学遗传工程国家重点实验室、现代人类学教育部重点实验室、遗传与发育协同创新中心的张锋教授和北京协和医院的邱贵兴院士是本文的共同通讯作者。吴南(协和)、明轩(复旦)、肖建球(复旦)、吴志宏(协和)及陈晓丽(首儿)是该论文的并列第一作者。该研究得到了科技部、国家自然科学基金委、教育部、以及复旦大学“2011协同创新中心”建设培育项目的资助。